Thrombocytopenia

Thrombocytopenia maybe defined as a subnormal number of platelets in the circulating

blood. It is the most common cause of abnormal bleeding. In general, the severity and

frequency of hemorrhagic manifestations correlate to the platelet count. Platelet counts

below 20×109/L usually are associated with spontaneous hemorrhage.

Thrombocytopenia results from three processes: (1) deficient platelet production. Those

that depopulate the stem cell or megakaryocyte compartments are the most common, e.g.,

marrow injury by myelosuppressive drugs or irradiation and aplastic anemia.(2) accelerated

platelet destrucion, utilizaton or loss, e.g., idiopathic thrombocytopenia purpura, diffuse

intravascular coagulaton, thrombotic thrombocytopenia purpura. (3) abnormal distribution or

pooling of the platelets within the body. This type of thrombocytopenia is seen in the various

disorders associated with splenomegaly.

Idiopathic thrombocytopenic purpura

Idiopathic thrombocytopenic purpura ia an acquired disease of children and adults

characterized by a low platelet count ,an normal or increased numbers of megakaryocytes in

the bone marrow, and absence of evidence for other disease. Although this disease is also

referred to as immune thrombocytopenic purpura and autoimmune thrombocytopenic

purpura, idiopathic thrombocytopenic purpura remains the most common designation. The

clinical syndromes of ITP are divided into acute and chronic types.

[Etiology and pathogenesis]

Evidence is mow convincing that the syndrome of ITP is caused by platelet destruction

as the result of an immunologic process.

1. Platelet survival

Platelet survival is greatly shortened in ITP. The survival time of isologous platelets

labeled with 51Cr-chromate ranges from 2 to 3days to a matter of minutes.

2. Platelet antibodies

Thrombocytopenia in ITP appears to result from the action of a platelet antibody. The

infusion of plasma from patients with ITP predictably induces thrombocytopenia in normal

recipients. The responsible factor is an immunoglobulin of the IgG class that is species

specific. Increased quantities of IgG have been demonstrated on the platelet surface, and the

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rate of platelet destruction in ITP is proportional to levels of such platelet-associated IgG.

3. Immune complexes

The frequency with which acute ITP is associated with antecedent viral infection have

led to the suggestion that a viral antigen-antibody complex, may be responsible for platelet

sensitization and destruction in this form of the disorder.

4. Role of the spleen

When 51Cr-chromate-labeled isologous platelets are administered to patients with ITP,

external scintillation counting reveals a rapid accumulation of radioactivity predominantly in

the spleen. Platelet phagocytosis by splenic leukocytes has been demonstrated in vitro.

Hepatic sequestration of platelets has been demonstrated in association with ITP, usually in

patients with severe thrombocytopenia and markedly shortened platelet survival.

The spleen also is important in ITP as a site of production of platelet antibodies.

Splenic tissue from patients with ITP produces more immunoglobulin than that of normal

control subjects, and a significant percentage of that formed binds to homologous platelets.

5. Impaired thrombopoiesis

In chronic ITP, an immunoglobulin has been demonstrated on the surface of the

megakaryocytes by means of immunofluorescence and other techniques. Conceivably, the

attachment of antibody may impair platelet production. Thus, total megakaryocyte mass and

the platelet turnover rate were several times greater than normal.

[Clinical features]

1. Acute ITP

Acute ITP occurs most frequently in children 2 t0 6 years, it rarely affects adults and has

no gender predilection. In patients with acute ITP, the onset of the disorder usually is sudden.

A history of infection preceding the onset of bleeding has been documented repeatedly.

Acute ITP usually is self-limited; spontaneous remissions occur in as many as 93% of

patients. The duration of the disease ranges from a few days to a few months, with an

average of 4 to 6 weeks.

2. Chronic ITP

Chronic ITP affects persons of all ages, but it is relatively more common between puberty

and 50 years of age. It occurs more frequently in women than in men, a ratio of

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approximately 3:1 having been found repeatedly. The onset of the chronic form of the

disorder usually is insidious. Patients usually have a fluctuating clinical course. Episodes of

bleeding may last a few days of a few weeks, and may be intermittent or even cyclic.

Spontaneous remissions are uncommon and are likely to be incomplete.

3. Bleeding manifestation

Bleeding into the skin in the form of petechiae is characteristec. Petechiae are

asymptomatic, not palpable, and occur most in dependent region. Symptoms and signs are

predictable from the known pattern of bleeding associated with platelet disorders: purpura,

menorrhagia, epistaxis, and gingival bleeding are common; gastrointestinal bleeding and

hematuria are less common. Intracerebral hemorrhage is uncommon, but it is the most

common cause of death and may occur acutely or at any time during a prolonged course.

4. Others

Repeated bleeding may lead to anemia of iron deficiency type. The spleen is occasionally

palpable on deep inspiration but never greater.

[laboratory Finding]

1. The blood

Isolated thrombocytopenia is the essential abnormality. Abnormalities in platelet size

and morphologic appearance are common. The platelets often are abnormally large, e.g., 3 to

4μm in diameter, and reveal more than normal variation in size and shape. Other

morphologic changes may be seen in some patients, e.g., “giant”forms (10μm or more in

diameter), bizarre shapes, and deeply stained forms. The white blood cell count and

hemoglobin concentration are usually normal unless significant hemorrhage due to the

thrombocytopenia has occurred. Eosinophilia of blood and marrow may be noted, but this is

more common in the acute ITP of childhood.

Tests of hemostasis and blood coagulation reveal only changes attributable to

thrombocytopenia, such as a prolonged bleeding time, absent or deficient clot retraction, a

positive reaction to the tourniquet test, and deficient prothrombin consumption. The results

of tests of blood coagulation, e.g., prothrombin time, partial thromboplastin time, and

coagulation time, are normal in patients with uncomplicated thrombocytopenia.

2. The marrow

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Alterations in the bone marrow are limited to the megakaryocytes, with the exception

of the normoblastic hyperplasia that may develop as the results of blood loss. Increased

marrow megakaryocytes with a shift to younger, less polyploid megakaryocytes and fewer

mature, platelet-producing megakaryocytes has been commonly reported.

3. Tests for platelet antibodies

Assays of PAIgG represent the first sensitive and reproducible method for

demonstrating antibodies in ITP. PAIgG is increased in patients with ITP, and the magnitude

of increase is greater in patients with more severe thrombocytopenia.

[Differential diagnosis]

The diagnosis of ITP is made by excluding other causes of thrombocytopenia, e.g.,

acute infectious illness, myelodysplastic syndrome, hypersplenism, disseminated

intravascular coagulation, aplastic anemia, acute leukemia, systemic lupus erythematous.

Several differences exist between acute ITP and chronic ITP that are of particular

significance in the interpretation of data concerning the incidence of the disorder, its

prognosis, and the results of therapy (see Table).

Table. Features of acute and chronic ITP

Features Acute ITP Chronic ITP

Peak age incidence Children 2-6 years of age Adults, 20-40 years of age

Sex predilection None 3:1, female to male patients

Antecedent infection Common 1-3 weeks before

onset

Unusual

Onset of bleeding Abrupt Insidious

Hemorrhagic bullae in

mouth

Present in severe cases Usually absent

Platelet count <20×109/L 30-80×109/L

Duration 2-6 weeks; rarely longer Months or years

Spontaneous remissions Occur in 80% of cases Uncommon; fluctuating course

common

[Treatment]

Physical activity should be restricted to minimize the hazards of trauma, particularly

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head injury. Drugs that impair platelet functions should be avoided. Blood loss should be

treated as otherwise indicated.

Observation: Most patients who are incidentally discovered to have asymptomatic mild

or moderate thrombocytopenia can safely be followed with no treatment.

1. Corticosteroids

Corticosteroids are widely used as the initial means of therapy. Mechanism of action:

(1) significantly diminish immunoglobulin synthesis. (2) inhibit the binding of antibodies to

platelets. (3) impair reticuloendothelial function and thereby to diminish platelet destruction.

One commonly used in initiation therapy consists of administering 40 to 60mg of prednisone

daily to adults, and 1mg/kg body weight to children. The initial course of steroids should be

maintained for 3 to 4 weeks, followed by a gradual tapering of the dosage. Steroid therapy

should not be maintained for long periods, a reasonable rule of thumb being 6 months at

most. Some increase in platelet numbers and a favorable clinical response can be expected in

70 to 90% of patients with ITP who receive adrenal corticosteroid therapy. However, most

patients will relapse when prednisone is tapered or discontinued.

2. Splenectomy

The major effects of splenectomy are twofold: (1) removal of the major site of

destruction of antibody-sensitized platelets. (2) removal of a major site of antibody synthesis.

The indications for splenectomy in patients with ITP may be stated as follows: (1)

failure of spontaneous remission to occur after 6 months of observation in patients with

moderate or severe bleeding. (2) failure to respond to steroid therapy, relapse after

discontinuance of steroid therapy or reduction in the dosage, or the necessity of high doses

for maintenance of a clinical status free of serious hemorrhage. (3) difficulty in assuring

adequate follow-up care. (4) overriding contraindications due to the use of steroids.

Splenectomy is contraindicated in the following situations: (1) early in the first episode

of bleeding, especially in children, because of the frequency of spontaneous remissions. (2)

in patients with cardiac or other complications who are at risk of serious sequelae from any

major surgical procedure. (3) in children under 2 years of age, in whom the hazard of

fulminating infection after splenectomy is greater than at a later age. (4) in many cases of

ITP in pregnant women. (5) in patients with acute ITP and major uncontrolled bleeding in

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whom the mortality rate after splenectomy is high.

Most patients who will respond to splenectomy do so within several days. Complete

and sustained remissions have occurred after splenectomy in from 50 to over 90% of

patients. By measuring the pattern of splenic versus hepatic sequestration with radiolabeled

platelets may predict the response to splenectomy.

3. Immunosuppressive drugs

Cyclophosphamide (50 to 200mg/day orally or 300 to 600 mg/m2 intravenously every 2

weeks) has induced remissions in from 44 to 55% of patients.

Vincristine (0.025mg/kg not to exceed a total dose of 2mg) and vinblastine

(0.0125mg/kg), administered intravenously at weekly intervals, appear to be as effective as

cyclophosphamide, but act more rapidly.

Azathioprine, actinomycin, and other immunosuppressive agents, either alone or in

combination with corticosteroids, have been administered to patients with ITP, with variable

success. All of these immunosuppressive agents may be leukemogenic and/or carcinogenic.

4. Emergency treatment of acute bleeding

In patients with severe bleeding, in addition to conventional critical care measures,

appropriate treatment includes platelet transfusions, high-dose parenteral glucocorticoids,

and IVIg.

Platelet transfusions: Platelet transfusions may produce some increase in platelet

numbers in many patients, often diminish bleeding for a time, and can be effective in the

management of serious complications, e.g., subarachnoid hemorrhage. They should be

reserved for such life-threatening emergencies or for the immediate preoperative treatment

of patients with serious hemorrhage before splenectomy. In patients with platelet counts

above 50×109/L, preoperative platelet transfusions are not indicated. Platelet replacement

should be avoided in patients with chronic ITP because of the possible development of

alloantibodies.

High-dose immunoglobulin. The mechanism of this therapeutic effect is not entirely

clear, but most evidence points to blockade of the Fc receptors of the reticuloendothelial

cells, and perhaps neutralization of antiplatelet autoantibodies by antiidiotypic antibodies in

the preparations. A regimen of 400mg/kg/day for 5 days usually is recommended. Treatment

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with immunoglobulin appears to be effective in patients who failed to respond to

splenectomy, in pregnant women, and in some patients who are refractory to all other modes

of treatment.

High doses of glucocorticoids, such as 1 g of methylprednisolone given by intravenous

infusion daily for 3 days, may also cause a rapid increase of the platelet count and may

ameliorate bleeding even if platelet counts remain low due to an effect on the vasculature.

5. Others

Danazol, an androgen with minimal virilizing side effects, has proved effective in the

treatment of ITP. In doses of 400 to 800mg/day, presumably acts by inducing

reticuloendothelial dysfunction, possibly by diminishing Fc (IgG) receptors.

Exchange plasmapheresis. It may be valuable in critically ill patients, and may be

particularly effective in children.

Anti-D. Intravenous Rh (D) immune globulin has been studied in children with acute

ITP and refractory chronic ITP as an alternative to intravenous Ig. The mechanism of action

is unknown; however, it is believed that the antibody coats the red blood cells of Rh-positive

patients and either blocks the reticuloendothelial clearance of the patients platelets or

modulates the immune system, resulting in an increase in the platelet count. Children

respond better than adults, and nonsplenectomized patients respond better than

splenectomized patients. The only clinically important side effect of anti-Rh(D) is the

predictable alloimmune hemolysis.

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